The present invention relates to novel purine nucleoside analogues useful as antiviral agents. Particularly, the invention relates to purine nucleosides with improved pharmacokinetic properties.
In the United States, more than 12 million new cases of sexually transmitted diseases (STDs) occur each year. Of the top 10 reportable diseases in the United States, five are STDs including chlamydia, gonorrhea, syphilis, the Acquired Immune Deficiency Syndrome (AIDS) and hepatitis B virus (HBV) infection of which AIDS and HBV infection have no cures.
In the case of AIDS, the World Health Organization predicts that by the year 2000 there will be 40 million people worldwide infected with the human immunodeficiency virus (HIV), the virus that causes (AIDS). Hepatitis infections affect 5 times more people that HIV. It has been reported by the World Health Organization that 2000 million people alive today are infected with HBV virus, of whom 350 million are chronically infected and therefore at risk of death from liver disease.
Although mortality rates from AIDS are dropping due to new therapies, AIDS remains the second leading cause of death in adults between the ages of 29 and 40. Combination anti-HIV therapy is now the standard of care for people with HIV. There are now 11 anti-HIV drugs available by prescription. These anti-HIV drugs fall into three categories: nucleoside analogs, which include zidovudine, didanosine, zalcitabine, stavudine or lamivudine; protease inhibitors which include indinavir, nelfinavir, saquinavir and ritonavir and non-nucleoside reverse transcriptase inhibitors (NNRTI) which include nevirapine, delavirdine and efavirenz. Compared to HIV, there is presently only few licensed therapy for chronic hepatitis B virus infection which are interferon and lamivudine. Other drugs are currently under clinical trials including, famciclovir, lobucavir and adefovir. But many studies have shown that most patients relapse after completion of therapy and develop resistance to the drugs.
Development of resistance has recently become a major concern in the treatment of HIV and HBV infections. Resistance usually occurs when the drugs being used are not potent enough to completely stop virus replication. If the virus can reproduce at all in the presence of drugs, it has the opportunity to make changes in its structure, called mutations, until it finds one that allows it to reproduce in spite of the drugs. Once a mutation occurs, it then grows undetected and soon is the dominant strain of the virus in the individual. The drug becomes progressively weaker against the new strain. There is also increasing concern about cross-resistance. Cross-resistance occurs when mutations causing resistance to one drug also cause resistance to another. Several studies have proven that combining two drugs delays the development of resistance to one or both drugs compared to when either drug is used alone. Other studies suggest that three-drug combinations extend this benefit even further. As a result, many people believe that the best way of preventing, or at least delaying resistance is to use multi-drug combination therapies. But as the number of drugs increases, so does the risk or drug interactions and toxicity.
One way to increase the efficacy of a drug is to improve its pharmacokinetic properties which contribute to its therapeutic activity. The science of pharmacokinetics is the study of the factors which determine the amount of chemical agents at their sites of biological effect at various times after the application of an agent or drug to biological systems. Pharmacokinetics includes study of drug absorption and distribution (xe2x80x9cbiotranslocationxe2x80x9d), study of the chemical alterations a drug may undergo in the body (xe2x80x9cbiotransformationxe2x80x9d), and study of the means by which drugs are stored in the body and eliminated from it. In chronic drug therapy, bioavailability is the more important factor because it relates to the extent to which a drug is absorbed and reaches the bloodstream or is otherwise available to the treatment site in the body. The bioavailability is directly linked to the drug ability to dissolve in biological fluids.
(xe2x88x92)-xcex2-D -2,6-diaminopurine dioxolane (DAPD) and (xe2x88x92)-xcex2-D -1,3-dioxolane guanine (DXG) have been reported to have a high efficacy against HIV-1 in various cell systems, minimal cross resistance with lamivudine and low toxicity. However, these compounds have poor pharmacokinetic properties which could be improved. It would therefore be useful to be provided with compounds having improved pharmacokinetics for use in the treatment of patients infected with HIV and HBV.
In one aspect, the present invention provides novel purine cis-nucleoside compounds represented by formula (I): 
and pharmaceutically acceptable salts thereof,
wherein:
n is 1 or 2
R4 is chosen from H, COOH, CONH2, OH, SH, NH2, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, CORa wherein Ra is a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or COORb wherein Rb is a C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl;
R3 is H or a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl;
X is chosen from H, monophosphate, diphosphate, triphosphate, carbonyl substituted with a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, or 
wherein each Rc is independently chosen from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or an hydroxy protecting group; and
wherein said nucleoside is present in the form of the (xe2x88x92) enantiomer, the (+) enantiomer and mixtures thereof, including racemic mixtures.
The compounds of the present invention are useful in therapy, in particular as antivirals.
In another aspect, there is provided a method of treating viral infections in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of a compound or composition of the invention.
In another aspect, there is provided a pharmaceutical formulation comprising the compound of the invention in combination with a pharmaceutically acceptable carrier or excipient.
Still another aspect, there is provided a method of treating viral infections in a subject in need of such treatment comprising administering to the subject a combination comprising at least one compound according to formula I and at least one further therapeutic agent chosen from nucleoside analogues; non nucleoside reverse transcriptase inhibitors (NNRTIs); or protease inhibitors.
In still another aspect, there is provided a pharmaceutical formulation comprising at least one compound according to formula I, at least one further therapeutic agent chosen from nucleoside analogues; nonnucleoside reverse transcriptase inhibitors (NNRTIs); or protease inhibitors, and a pharmaceutically acceptable carrier or excipient.
In another aspect of the invention is the use of a compound according to formula I, for the manufacture of a medicament for the treatment of viral infections.